Nu-substituted poly-iodo phthalimides



Patented May 23, 1950 N-SUBSTITUTED POLY-IODO PHTHALIMIDES William H.Strain, Rochester, N. Y., and Joseph Dec, Martinsville, N. J., assignorsto Eli Lilly and Company, Indianapolis, Ind., a corporation of IndianaNo Drawing.

6 Claims. 1

Our invention relates to novel compositions of matter suitable forroentgenologic studies and more particularly to novel iodinatedphthalimide derivatives.

Objects of our invention include the provision of radiopaque substancessuitable for introduction in the gastrointestinal tract and which whenso introduced will form an even coating on the interior of the tract butwhich will not be appre ciably absorbed, nor cause any disturbance ofthe tract which would prevent an accurate roentgenologic portrayalthereof. Other objects include the provision of radiopaque substanceswhich when suitably introduced in the gastrointestinal tract willdelineate the walls of the tract so clearly that any lesions thereonwill be observable; Other objects will become apparent as the followingdescription proceeds.

In accordance with our invention'we provide radiopaque substancescomprising novel iodin'ated phthalimide derivatives which may berepresented by the following formula wherein a: is a whole integer from2 to 4; and R; is a member of thegroup consisting of aliphatic groupshaving from 1 to 5 carbon atoms and alkoxyaliphatic groups having from 2to 5 carbon atoms. r

Illustrative phthalimide derivatives within the scope of the aboveformula are 3,6-diidophthalimidomethane, a (3,4,6 triiodophthalimido)-'ymethoxybutane, 3,4,5,6-tetraiodophthalimido-isopentane, 3,4,5,6tetraiodophthalimido-butene-2;' and3,4,6-triiodo-phthalimido-p-methoxypropane.

It will be noted that the above-represented novel compounds contain arelatively large proportion of iodine. The high iodine content isdesirable since it is the iodine which confers an opacity to X-rays;Accordingly, our preferred phthalimide derivatives are those which aretetra-v iodinated; that is, those which contain four iodine atoms in thebenzene ring of the phthalimide por-- tion of the molecule. We havediscovered that; the high iodine content not only confers upon thephthalimide derivatives a high degree of; opacity to X-rays, but alsoremarkably reduces their solubility thus preventing their absorption bythe intestinal tract which would make them. unsuitable for;gastrointestinal roentgenologic purposes. ,Weare aware that AllenandNicholls Application December 4, 1947, Serial No. 789,764 1 in J. Am.Chem, so 56, 1409 (1934) have described certain chlorinated phthalimidederivatives. However, these derivatives not only lack the necessaryopacity to X-rays, but also fail to possess the low solubility requiredfor satisfactory performance as gastrointestinal radiopaque sub stances.Moreover, the method described by Allen et a1. is unsuitable for thepreparation of our derivatives.

To prepare our novel phthalimide derivatives we react an iodinatedphthalic anhydride with a formamide in which the amide nitrogen has as asubstituent the appropriate aliphatic or alkoxyaliphatic group. Duringthe reaction the oxygen atom in the phthalic anhydride molecule isreplaced by the aliphatic amino or alkoxyaliphatic amino group of thesubstituted formamide, and the desired phthalimide derivative isproduced.

Iodinatedphthalic anhydrides which we may use as starting materials areknown to the art and their method of preparation has been de-- scribedby Pratt and Perkins [J, Am. Chem. Soc. 40, 198 (1918)] and by Pratt andShupp [J. Am; Chem Soc. 40, 254 (1918) 1. Some of the iodinated phthalicanhydrides are available commercially; The formamides used in preparingour compounds are readily available by methods of preparation known tothe art, for example, the method of Linnemann [J. Chem. Soc. 1869, 601].

The process of preparing our novel phthalimide derivatives is set out indetail in the following specific examples. a

I Example 1 Preparation of 3,4,5,6-tetraiodophthalimido methane.

326 parts of tetraiodophthalic anhydride (commercially obtainabletechnical grade) and 590 parts of N-methylformamide are mixed togetherand heated with stirring to -160 C. for about onevhour. As the reactionproceeds, some of the 3,4,5,6-tetraiodophthalimidornethane separates. asa solid. The reaction mixture is cooled to about room temperature andthe 3,4,5 .6-tetraiodophthalimidomethane which separates in excellentyield in the formlof a yellow powder isrfiltered off. It is purified bysuspending .it in water, filtering the suspension and washing thesolid.3,4,5,6-tetraiodophthalimidomethane which collects on the filter,with water and. alcohol. The product so obtained melts at about 300 C.

The technical grade of tetraiodophthalic anhydride used in the abovepreparation contains small amounts of diand triiodophthalic' anhydrideand consequently :the 3,4,5,6.-tetraiodo;-.

phthalimidomethane is contaminated with some diandtri-iodophthalimidomethane. If the pure tetraiodo compound is desired,pure tetraiodophthalic anhydride should be employed in the reactionsinceit: is difil'cult to purify-the tetraiodoe phthalim'ido compound bycrystallization. For the purposes of this invention, however, a mixtureprepared according to the above procedure is emi:-' nently satisfactory.

Example 2 3,6-diiodophthalimidomethane is? prepared--.

from 3,6-diiodophthalic anhydride. and. N-

methylformamide by the procedureidescribedin- Example 1 for thepreparation of the tetraiodinated phthalimide derivative.

Example 3 methanol and. thee smalhamiounteofl nitrobenzeneentrained: in.the solid is. removed bysubjecting the-solid to steamdistillationforabout one. half hour. The: residue: of3,4,5,6-tetraiodophthalimidomethane' is separated from. the waterbyfiltration and dried. The product so obtained melts. atabout 313-618.C. Uponrecrystal-lizationfrom chlorobenzene-the product is obtained insubstantially pure form andmeits. at about 325-327? C.

In placeotthe nitrobenzene-employed in. the above example; otherdiluents or: extending agents will be apparent torone; in the art.Suitable. agents include cumene, isocnmene; xylene, chlorobenzene andanisole. If desired; ethanol, butyl. ether and. thalike may be used asdiluents and the: reaction carried out in a closed system to permit; asufiicientdegree of heat to be applied to the reactions When no diluentemployedittle desirable to use an amount of the formamide su-fiicient toserveboth as a reagent and a diluent. In either event, an excess-oitheformamide should be present inthe. reaction mixture to insure thecomplete reaction of the iodin'atedphthalic anhydride.

Example 4' Preparation of- 33.5.6-tetraiodophthalimido-- ethane;

A mixture of 326'. parts: of 3-,4,5,-6-tetraiodophthalic anhydrideand.730 parts of. N- ethylformamide is'heated' with. stirring at 150- 160?-C; for about one hour. The '3:,4=,5,6-tetra-- iodophthalimidoethanewhich. is formed: durin j the. reaction. is isolated and purified by'thepro.-

cedure. described in Example 1'. 3A,5;6.-tetraiodophtha'limidoethaneeso. obtained melts with.

. decomposition at about 310 C." a

V isopropane.

A: mixture; at 326" partsof 3 ,4 ,5,-fi-:-tetraa iodophthalic.anhydridea. and:-.8-T01 parts:.:. of: 1 1- ma n isopropylformamide isheated with stirring at 150-160 C. for about one hour. The yellowprecipitate of 3,4,5,6-tetraiodophthalimidoisopropane obtained in thereaction mixture is. isolated and-purified by the procedure described inExample 1. The 3,4,55-tetraiodophthalimi- .doisopropane so obtainedmelts with decomposition at about 305-310 C.

" dOpropene-Z.

Iirl-vatives maybe administered in the form. of.

TheN-isopropylformamide used in the reaction may be prepared by themethod of Linnemann [J. Chem. Soc. 1869, 601]. The com- ,pound'whichboilsat about C. at 20 mm.

pressure hasbeen described by Gautier [Ann Example 6 Preparation of3,4,5,6-tetraiodophthaliml- Ar mixture of 400 parts of N-allylformamidewhich may be prepared by the method of Clayton [Be1...28, 1666(1895)],,. and. lfiflparts of 3,4, 5;6'tetraiodophthalic, anhydride, isreacted ac: cordin to the procedure. described in, Example I; The3,4,5,6 tetraiodophthalimidopropenefl so obtained melts vvith,vdecomposition, atabout Example. 7

Preparation; of a:(SAfifi-tetraiodophthafiimidoy-p-methoxyeth-ane.

Nae-rnethoxyethylfonnamider which boils at about 112" Q. at. 18::mm.pressure andwhich is prepared in the. usual manner; is' reacted; with3%,5',fi-tetraiodophthalic: anhydride; in. the. proportions: of:- andaccording: to; the: procedure 1 described 1 Example. 1 Thee-(tetraiodophthali- 'mido)--fl-.-methoxyethane thus prepared meltsEurthermore,;.unlike barium sulfate, ourphtha'l ide derivative produceno insipissation of the bowel wall which causes confusion" in. theinterpretation-0t roentgenographs; Ourrphthalim idederivativeshave aremarkably. low toxicity when'given: orally; For: example, oral.administration of 3,4','5,6 tetraiodophthalimidomethane to: fastingratsiinam'ourits'up to g; per kilo-z ing or normative condition of thebowel" is de-j sired.

For -radiopaquepunposes; our phthal'imi-dedemoans aqueous suspensions.For such administration the derivatives are reduced to a finely dividedstate, desirably to a particle size less than about 1 micron. This finedivision may be obtained by methods known to the art, for example, bygrinding, ball milling, or by passing an aqueous sus- {pension of thecompound through a suitable colloid mill. We'have found that aqueoussuspensions containing from 15 to 30 percent oi .our iodinated compoundsform stable suspensions which in themselves are not unpleasant to takeand which, if desired, may be made yet more palatable by the addition orsmall amounts of .a flavoring agent.

1 6 C N (Dr- -R 4 0/ wherein a: is a whole integer from 2 to 4, and R isa member of the group consisting of aliphatic groups having from 1 to 5carbon atoms and 'alkoxyaliphatic groups having from 2 to 5 carbonatoms.

2. 8,4,5,6-tetraiodophthalimidoalkanes wherein the alkane portion or themolecule has from 1 to 5 carbon atoms.

3. 3,4,5,6-tetraiodophthalimidomethane.

4. 3,4,5,6-tetraiodophthalimidoethane.

5. 3,4,5,6-tetraiodophthalimidoisopropane.

6. Radiopaque compositions comprising compounds according to claim 1 infinely divided state, suspended in aqueous media.

WILLIAM H. STRAIN. JOSEPH DEC.

REFERENCES CITED The following references are of record in the file orthis patent:

UNITED STATES PATENTS Name Date Strain et a1. Oct. 19, 1948 OTHERREFERENCES Number

1. IODINATED PHTHALIMIDE DERIVATIVES REPRESENTED BY THE FOLLOWINGFORMULA